Lower alkoxy



United States Patent 3,256,286 3 HYDROXY 6 OX0 N LOWER ALKYLMOR- PHINANS AND 3 LOWER ALKOXY 4 ARYL- OXY 6p HYDROXY N LOWER ALKYLMOR- PHINANS Yoshiro Sawa and Shin Maeda, Hyogo Prefecture, and Naoki Tsuzi, Osaka Prefecture, Japan, assignors to Shiouogi & Co. Ltd., Osaka, Japan N0 Drawing. Filed Apr. 4, 1963, Ser. No. 270,554 Claims priority, application Japan, Apr. 9, 1962, 37/ 14,252 4 Claims. (Cl. 260-285) The present invention relates to a process for hydrogenation of morphinan derivatives and products thereby.

In the term morphinan herein employed, there are included all the compounds having a fundamental structure representable by the following plane formula:

Accordingly, the term morphinan means not only normal morphinan (cis-1,3,4,9,10,10a-hexahydro-ZH-IOAaiminoethanophenanthrene) but also isomorph-inan (trans- 1,3,4,9,10,10a hexahydro 2H 10,4a iminoethanophenanthrene), inclusively. When distinction is necessary, normal morphinan and isomorphinan will be hereinafter designated as morphinan (cis) and morphinan (trans), respectively. The position-numbering hereinafter employed for the morphinan derivatives is that generally accepted in morphinan chemistry as shown in the above plane formula.

The hydrogenation process of the present invention is illustratively representable by the following formulae:

RO- R0 wherein R represents a hydrogen atom, a lower alkanoyl group (e.g. \acetyl, propionyl, butyryl) or a lower alkyl group (e.g. methyl, ethyl, propyl), R represents a hydrogen atom, an aryloxy group (e.g. phenyloxy, naphthyloxy) or a substituted aryloxy group (e.g. substituted phenyloxy, substituted naphthyloxy) wherein the substituent is lower alkyl (e.g. methyl, ethyl, propyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy), nitro or amino, R" represents a hydroxymethylene. group, a lower alkanoyloxymethylene group (e.g. acetyloxymethylene, propionyloxymethylene, butyryloxymethylene), a carbonyl group or a ketalated carbonyl group (e.g. ethylene- 3,255,286 Patented June 14, 1966 "Ice dioxymethylene, diethoxymethylene), R' represents a lower alkyl group (e.g. methyl, ethyl, propyl) or an ar(lower) alkyl group (e.g. benzyl, phenethyl) and X represents a hydrogen atom, a hydroxyl group or a lower alkanoyloxy group (e.g. .acetyloxy, propionyloxy, butyryloxy).

As the starting material, there may be used the optically active or racemic A -morphinan of Formula I. Specific examples of the N-morphinan (I) include 3-hydroxy-6-oXoN-methyl-A' -morphinan,

3-acetyloxy-6-oXo-N-methyl-A' -morphinan,

3,6a-dihydroxy-4-phenyloxy-N-methyl-A"-morphinan,

3,6fl-dihydroXy-4-p-methoxyphenyloxy-N-methyl-A' morphinan, 3-methoxy-6-oxo-N-methyl-N-morphinan,

3-ethoxy-6-oXo-N-methyl-A -morphinan,

3-rnethoxy-6a-hydroxy-N-methyl-N-mo-rphinan, 3-methoxy-6 3-hydroXy-N-methyl-A -morphinan, 3-methoxy-6,8 acetyloXy-N-methyl-N-morphinan, 3-methoxy-4-phenyloxy-6-oxo-N-methyl-A' -morphinan, 3-methoxy-4-phenyloxy-6a-hydroxy-N-methyl-A' morphinan, 3-methoxy-4-phenyloxy-6B-hydroxy-N-methyl-A morphinan, 3, l4-di=hydroxy-6-oxo-N-methyl-A' -morphinan, 3-hydroXy-6-oXo-N-ethyl-A -morphinan, 3-l1ydroxy-6-oXo-N-phenethyl-N-morphinan, 3 ,6ot, 14-trihydroxy-N-methyl-N-morphin an, 3-rnethoxy-6-oxol4-hydroxy N-methyl-A' -morphinan, 3-methoXy-6-oxo-14-acetyl-oxy-N-methyl-A -morphinan, 3-methoXy-6-oxol 4-acetyloxy-N-phenethyl-A' morphinan, 3-methoxy-4-phenyloxy-6a,14-dihydroXy-N-methy1-A morphinan, 3 -methoXy-4-phenyloXy-6 u, 14-diacetyloXy-N-methyl-A' morphinan, etc.

According to the process of the present invention, the starting A -morphinan (I) is subjected to hydrogenation to produce the morphinan of Formula II. Although various conventional hydrogenation procedures can be adopted for attaining the object, the application of catalytic hydrogenation is preferred. For instance, the

hydrogenation reaction may be eifected by treating the N-rnorphinan (I) with hydrogen in the presence of a catalyst such as platinum catalyst (e.g. platinum, platinum dioxide, platinum black, platinum-carbon), palladium catalyst (e.g. palladium, palladium monoxide, palladium-black, palladium carbon, palladium-strontium carbonate, palladium-barium sulfate) and nickel catalyst (e.g. Raney nickel, Urushibara nickel) in an inert solvent medium (e.g. water, methanol, ethanol, ether, tetrahydrofuran, dioxane, benzene, acetic acid), usually at room temperature (15 to 30 C.) under atmospheric pressure.

The morphinan (11) occurs in optically active form as well as in racemic mixture and these are all within the scope of the present invention. Specific examples of the morphinan (II) include 3-hydroxy-6-oxo-N-methylmorphinan, 3-acetyloXy-6-oXo-N-methylmorphinan,

- 3 3 ,6a-dihydrxy-N-methylmorphin an, 3-hydroxy-6a-acetyloxy-N-methylmorphinan, 3 ,6ot-diacetyloxy-N-methylmorphinan, 3 ,6 ,B-dihydroxy-N-methylmorphinan, 3 -hydr0xy-4-phenyloxy-6-oxo-N-methylmorphinan, 3-acetyloxy-4-phenyloxy-6-oxo-N-methylmorphinan, 3-propionyloxy-4-phenyloxy-6-ox0-N-methylmorphinan, 3-hydroxy-4-p-nitrophenyloxy-6-oxo-N-methylmorphinan, 3 ,6a-dihydroxy-4-phenyloxy-N-me-thylmorphinan, 3,6,B-dihydroxy-4-p-methoxyphenyloxy-N-methylmorphinan, 3-methoxy-6-oxo-N-methylmorphinan, 3-eth0xy-6-oxo-N-methylmorphinan, 3-methoxy-6u-hydroxy-N-methylmorphinan, 3 -methoxy-673-hydroxy-N-methylmorphinan, 3 -methoxy-6[3-acetyloxy-N-methylmorphinan, 3-methoxy-4-phenyloxy-6-oxo-N-methylmorphinan, 3-methoxy-4-phenyloxy-6a-hydroxy-N-methylmorphinan, 3-methoxy-4-phenyl0xy-6B-hydroxy-N-methylrnorphinan, 3,14-dihydroxy-6-oxo-N-rnethylmorphinan, 3-hydroxy-6-oxo-N-ethylmorphinan, 3-hydroxy-6-oxo-N-phenethylmorphinan, 3 ,6a, l4-trihydroxy-N-methylmorphinan, 3-methoxy-6-oxo-14-hydroxy-N-methylmorphinan, 3-methoxy-6-oxo-14-acetyloxy-N-methylmorphinan, 3 -methoxy-6-oxo-14-acetyloxy-N-phenethylmorphinan, 3-methoxy-4-phenyloxy-6a,14-dihydroxy-N-methylmorphinan, 3-methoxy-4-phenyloxy-6a, l 4-diacetyloxy-N-methylmorphinan, etc.

The morphinan (II) forms acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrohalide (e.g. hydrochloride, hydrobromide, hydroiodide), sulfate, phosphate, nitrate, tartrate, salicylate, benzoate, malate, citrate, acetate, etc.

The morphinan (II) and acid addition salts thereof exhibit various pharmacological activity such as analgesic act1v1ty, antitusslve act1v1ty and antunflammatory activity. For lnstance, the analgesic act1v1ty and toxlcity of some morphman compounds according to the present invention are shown In the following Table I:

TABLE I Analgesic activity Toxicity Compound (LD U,

Hafiner DAmour mgJkg.)

Hesse Smith method method -3-methoxy-6-oxo-N-methylmorphinan (cis) hydrochloride 2. 7 1. 54. 02 ()-3-hydroxy-6-oxo-N-methylrnorphinan (cis) tartrate 1. 8 1. 2 86. 13 (-)-3-methoxy-fifl-acetyloxy-N- methylmorphinan (cis) 1. 0 1. 6 6. 95 ()-3,6B-diacetyloxy-N-methylrnorphinan (cis) 1. 4 11.0 91. 76 ()-3-rnethoxy-6-ox0-14-hydroxy-N-methylmorphinan (cis 4. 0 6.0 76. 77 (-)-3-rnethoxy-6-oxo-14-acctyloxy-N-rnethylmorphinan (cis) hydrochloride 3. 4 29. 9 1,000 (-)-3,14-dihydroxy-6-oxomethylmorphinan (cis) 5. 4 16. 5 150.20 ()-3-methoxy-6-oxo-14-hydroxy-N-phcnethylmorphinan (cis) 5. 7 10. 3 1, O00 ()-3,14-dihydr0xy-6-oxo-N- phenethylmorphinan (cis) 9. 4 43. 7 1, 000

NOTE: The analgesic activity was observed by the Hafiner-Hesse method [Hesset Arch. exp. Path. u..PharIn., Vol. 158, p. 233 (1930)] in mice and the DAmour-Smith method [DArnour et al.: J. PharmacoL, Vol. 1, p. 255 (1946)] in rats and is shown as the efiective ratio to morphine, the value of which is expressed as 1. The toxicity was tested by administering intravenously the tested compound to mice.

Further, for instance, the antitussive activity and toxicity of some morphinan compounds according to the present invention are shown in the following Table II:

TABLE II Anti- Toxicity Compound tussive (LD u,

activity rug/kg.)

()-3-methoxy-Gfl-hydroxy-N-methylmorphinan (cis) 2.0 82.51 ()-3-methoxyfl-acetyloxy-N-methylmorphinan (cis) 5.0 6. )-3'meth0xy-6a-acetylox N-methyldr 2. 7 37. 74

-3-hy oxy-fi-oxo- (cis)tartrate 2. 9 86. 13 ()-3,6a-dihydroxy-N-methylmorphinan (cis) e 1. 4 172. 36 (-)-3-hydroxy-Ga-acetyloxy-N-methylmorphinan (cis) 1. 9 73. 55 (-)-3,6a-diacetyloxy-N-methylmorphinan (cis) 5. 2 45. 12 ()-3,65'diacetyloxy-N-methylmorphinan (cis) 2. 9 91. 76 ()-3-methoxy-fifi-acetyloxy-l l-hydroxy-N- methylmorphinan (cis) 2. 8 45. 20 ()-3-methcxy-6fl,14-diacetyloxy-N-methylmorphinan (cis 3. 4 72.11 ()-3methoxy-6a,14-diacetyloxy-N-methylmorphinan (cis) 1. 6 74. 02 ()-3-methoxy-6-oxo morphinan (cis) 16.0 76. 77 ()-3,14-dihydroxy-6-oxo-N-methylmorphinan (cis) 6.8 150. 20

NOTE: The antitussive activity was observed by the Winter method [Winter et al.: J. Exper. Med., Vol. 101, p. 17 (1955)] in guinea pigs and is shown as the effective ratio to codeine, the value of which is expressed as 1. The toxicity was tested by administering intravenously the tested compound tomice.

Accordingly, they are useful as analgesic and/or antitussive agents.

Practical and presently preferred embodiments of the present invention are illustrated by the following examples. In the examples, mg.=milligram(s), g.=gram(s),

To a solution of ()-3-methoxy-6-oxo-N-methyl-A' morphinan(cis) (290 mg.) in methanol (5 ml.), there is added palladium-carbon prepared from palladium chloride mg), activated carbon (200 mg.) and 5% hydrochloric acid (2 ml.), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (1.4 molar equivalent), the reaction mixture is filtered to separate the catalyst and distilled to remove ethanol. The residue is crystallized from ethanol to give ()-3-methoxy-6-oxo- N-methy1m0rphinan(cis) (147 mg.) as crystals melting at 187 to 188 C. 95.3 (ethanol).

Anal.Calcd. for C H O N: C, 75.76; H, 8.12; N,

4.91. Found: C, 75.82; H, 8.19; N, 4.81.

The starting material of this example, (-)-3-methoxy- 6-oxo-N-methyl-N-morphinan(cis), is prepared from -3,6-di1nethoxy-N-methyl-A -morphinan(cis) [Sawa et al.: Tetrahedron, Vol. -15, p. 154 (1961)] according to the following scheme:

CH30 CH3O N-CH3 ir-ona CHQO 0- EXAMPLE 2 Preparation of -3-hydr0xy-6-0x0-N- methylm0rphinan(cis) NCH N-CH;

)-3-hydroxy-6-oxo-N-methyl-A' -morphinan(cis) (60 mg.) is subjected to hydrogenation using palladium carbon as in Example 1 whereby there is obtained ()-3-hydr-oxy-6-oxo-N-methylmorphinan(cis) (60 mg.) as crystals melting at 227 to 228 C. (crystallized from tert. amyl alcohol). [a1 l(ll.5 (ethanol).

Anal.Calcd. for C17H21O2NC5H12OZ C, H, 9.25; N, 3.90. Found: C, 73.57; H, 9.32; N, 3.81.

The starting material of this example, ()-3-hydroxy- 6-oxo-N-methyl-A' -m0rphinan(cis), is prepared from -3 -methoxy-6-oxo-N-methyl-A -morphinan (cis) [cf Example 1 of this specification] according to the following scheme:

AIBIQ N-CH3 CHaO 3-methoxy-6-oxo-N-methyl-A -morphinan(trans) (300 mg.) is subjected to hydrogenation using palladium carbon as in Example 1 whereby there is obtained 3-methoxy-6-oxo-N-methylmorphinan(trans) (301 mg.) as a solid melting at 88 to 89 C. The solid is treated with picric acid in ethanol and crystallized from ethanol to give -3 -methoxy-6-oxo-N-methylmorphinan (trans) picrate as crystals melting at 236 C. [a] 8l.4:2 (ethanol).

Anal.Calcd. for C H O N-C H3O N C, 56.03; H, 5.09; N, 10.89. Found: C, 56.15; H, 5.28; N, 10.75.

The starting material of this example, (+)-3-methoxy- 6-oxo- N-methyl-A' -mo'rphinan(trans), is prepared from )-3,6-dimethoxy-N-methyl-A -morphinan (cis) [Sawa et al.: Tetrahedron, vol. 15, p. 154 (1961)] according to the followingscheme: p

To'a solution of (-|-)-3-methoxy-6a-hydroxy-N-methyl-A' -morphinan(cis) (50 mg.) in 99% ethanol (1- 1111.), there is added 5% palladium-strontium carbonate (30 mg), and the resulting mixture is shaken at room tem- .perature to C.) in hydrogen stream. After absorption of the theoretical amount of hydrogen, the reaction mixture is filtered to remove the catalyst and distilled to remove ethanol. The residue is crystallized from ethyl acetate to give (-)-3-methoxy-6a-hydroxy- N-methylmorphinan(cis) (48 mg.) as crystals melting at 133.5 to 134' C. --31.3 (ethanol).

Anal.--Cal-cd. for C H O N: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.22; -H, 8.73; N, 4.95.

The starting material of this example, (+)-3-methoxy- 6a-hydroxy-N-methyl-N-rnorphinan(ci s), is prepared from -3-methoxy-6-oxo N-methyl-A' -rnorphinan (cis) [c.f. Example 1 of this specification] according to the folfrom -3 methoxy-6-oxo-N-methyl-A' morphinan (cis) [cf. Example 1 of this specification] according to the following scheme:

omo on o NCH3 NCH3 EXAMPLE 6 Preparation of ()-3-methoxy-4-phenyl0xy-6-0xo-N- methylmorphinan(trans) IjI-OH, I N-CH;

To a solution of (+)-3-methoxy-4-pheny1oxy-6-oxo-N- methyl-A' morphinanflrans) (3.75 g.) in'ethanol (100 ml.), there is added platinum dioxide (50 mg), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (2150 ml.) in 2 hours, the reaction mixture is filtered to separate the catalyst and distilled to remove ethanol. The residue is crystallized from ethanol to give ()-3- methoxy 4-phenyloxy-6-oxo-N-methylmorphinan(trans) (3.50 g.) as crystals melting at 156 C. 41.0 (chloroform) Anal.Calcd. for C24H2703N: C, 76.36; H, 7.21; N, 3.71. Found: C, 76.30; H, 7.28; N, 3.75.

The methiodide.-M.P., 227 to 228 C. (crystallized from acetone).

The starting material of this example, (+)-3-methoxy- 4-phenyloxy-6-oxo-Nmethyl-A' -morphinan(trans), is prepared from -3,6-dimethoxy-4-phenyloxy-N-methyl- A -morphinan(cis) ['Sawa et al.: Tetrahedron, vol. 15, p.

164 (1961)] according to the following scheme:

8 EXAMPLE 7 Preparation of -3-meth0xy-6u-hydr0xy-N- methylmorphinan(trans) C a CHQO GHr C a L J ()-3-methoxy-6a-hydroxy N methyl-A' -morphinan (trans) is subjected to hydrogenation using platinum dioxide as in Example 6 whereby there is quantitatively obtained ()-3-methoxy 6u-hydroxy-N-methylmorphinan (trans) as crystals melting at 126 C. (crystallized from a mixture of methanol and water (1:1)). [@1 3 58.8 (chloroform) Anal.Calcd. for C H O N: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.97; H, 8.84; N, 4.56.

The starting material of this example, ()-3-methoxy- Gu-hYClIOXY N methylmor-phinan(trans), is prepared from (+)-3-methoxy-6-oxo-N methyl A morphinan (trans) [cf. Example 3 of this specification] according to the following scheme:

- Al(iso-C H1O)a N-CH3 EXAMPLE 8 Preparation 0 )-3-methoxy-6fl-hydr0xy-N- methylmorphinan(trans) CHsO CHsO C H, N-(] H3 HO HO ()-3-methoxy-6B-hydroxy-N-methyl A morphinan (trans) is subjected to hydrogenation using platinum dioxide as in Example 6 whereby there is obtained ()-3- methoxy-6,8-hydroxy-N-methylmorphinan(trans) as an oil. [a] -46.7 (chloroform). The oil is treated with picric acid in ethanol and crystallized from a mixture of ether and ethanol (1:1) to give ()-3-methoxy-6fi-hydroxy-N-methylmorphinan(trans)picrate as crytsals melting at 210 to 212 C. (decomp.).

Anal.-Calcd. for C1gH2502N'C H301N3: C, H, 5.46; N, 10.85. Found: C, 55.75; H, 5.79; N, 10.84.

The starting material of this example, ()-3-meth0xy- 6,8-hydroxy-N-methyl-A"-m0rphinan(trans), is prepared from 3 methoxy 6 oxo-N-methyl-A' -morphina 9. (trans) [cf. Example 3 of this specification]- according to the following scheme:

Preparation of -3-methoxy-4-phenyl0xy-6u-hydr0xy- N -methylmorphinan (cis) EXAMPLE 10 Preparation (-)-3-methoxy-4-phenyloxy-6 3-hydr0xy- N-CH;

N -methylm0rphinan (cis) 0 H3 0 C H3 O N-CH iq-oizt HO H0 3 methoxy-4-phenyloxy-6B-hydroxy-N-methyl- A -morphinan(cis) (200 mg.) is subjected tohydrogenation using platinum dioxide as in Example 6 whereby there is obtained 3-methoxy-4-phenyloxy 6,8 hydroxy- N-methylmorphinan(cis) (198 mg.) as crystals melting at 136 to 137 C. (crystallized from ether).

The starting material of this example, (+)-3-methoxy- 4-phenyloxy-6,8-hydroxy-1 I-methyl-A morphinan(cis), is prepared from (+)-3 -.methoxy-4-phenyloxy-6-oxo-N- methyl-A' -morphinamcis) [cf. Example 9 of this specification] according to the following scheme:

G E v CuHsO Al (lSO-C 3H70)3 N-CH;

o- 0 HO EXAMPLE 11 N-CH Preparation of )-3,6/3-dihydr0xy-N- methylmorphinan (cis) H0 HO N-CH v N H3 HO HO -3,6fl-dihydroxy-N-rnethyl-A' -morphinan cis) (32 mg.) is subjected to hydrogenation using platinum dioxide as in Example 6 whereby there is obtained (-)-3,6p-dihydroxy-N-methylmorphinan(cis) (31 mg.) as crystals melting at 243 to 244 C. (crystallized from acetone).

The starting material of this example, ()-3,6p-dihydroxy N-methyl-A -morphinan(cis), is prepared from )-3-methoxy 6/3-hydroxy-N-methyl-A' -morphina(cis) [cf. Example 5 of this specification] according to the following scheme:

omo HO AlBr;

N-om N-om What'is claimed is: 1. 3-hydroxy-6-oxo-N-lower alkylmorphinan. 2. -3-hydroxy-6-oxo-N-methylmorphinan (cis) 1 l 1 2 3. 3-1ower alkoxy 4 phenyloxy-GB-hydroxy-N-lowe: OTHER REFERENCES lalkylmorphman- Bentley, Chemistry of the Morphine Alkaloids, page 4. )-3meth0xy-4-pheny1oxy-6 3 hydroxy-N-methyl- 28, 338 5 morph1nan(c1s). 5 Gates et al., I. Am. Chem. Soc., vol. 78, pp. 1380-1393 (1956). kefeFencFs Clted by the Exammer Gates et al., J. Am. Chem. Soc., vol. 80, page 1186 UNITED STATES PATENTS (1958). 2 97 4 3/1961 Grussner et a1. 260'285 Hartung, Ind. Eng. Chem-, V01. 37, pages 126-127 3,085,091 4/1963 Sawa et a1 260285 3',144,4s9 8/1964 Sawa et a1 260.285

NICHOLAS S. RIZZO, Primary Examiner.

DON M. KERR, DONALD G. DAUS,

Assistant Examiners.

FOREIGN PATENTS 761,974 11/1956 Great Britain. 

1. 3-HYDROXY-6-OXO-N-LOWER ALKYLMORPHINAN
 3. 3-LOWER ALKOXY-4-PHENYLOXY-6B-HYDROXY-N-LOWER ALKYLMORPHINAN. 